Retinoic Acid / Retinoid Signalling Pathway
The Retinoic Acid / Retinoid Signalling Pathway Retinoic acid is derived from Vitamin A in the diet and is essential for many aspects of normal embryological and foetal development. Diagram of RA Pathway Figure Legend: An overview of the retinoic acid pathway is presented. Retinol is transported to target cells in a complex with RBP, with transfer into the cell occurring by the cell surface receptor STRA6. Within the target cell, retinol is bound to CRBP, and can be converted to retinal by ADH (in a reversible reaction), or to retinyl esters by LRAT. Retinal is oxidised to retinoic acid (RA) by RALDH in an irreversible reaction, whereby RA can complex with CRABP which enables transport to the nucleus. Within the nucleus RA forms a complex with RAR/RXR heterodimers, which in turn bind to a short DNA sequence, the retinoic acid response element (RARE) thereby activating transcription of the target gene. COUP-TFII can inhibit the heterodimerisation of RAR/RXR, thus inhibiting gene transcription. FOG2 interacts with both COUP-TFII and GATA4, thereby modulating the activity of GATA4 transcription factors. Excess cellular RA can be presented to CYP26 enzymes for degradation to Hydroxy RA. Nitrofen is believed to exert its effects through inhibition of RALDH activity. Abbreviations: RBP (retinol binding proteins). STRA6 (stimulated by retinoic acid 6). CRBP (cellular retinol binding proteins). ADH (alcohol dehydrogenases). RDH (retinol dehydrogenases). RALDH (retinaldehyde dehydrogenases). RA (retinoic acid). CRABP (cellular retinoic acid binding proteins). RAR (retinoic acid receptors). RXR (retinoid X receptors). RARE (retinoic acid response element). LRAT (lecithin:retinol acetyltransferase). CYP26 (cytochrome P450 family 26). Evidence For Involvement In CDH The Retinoid Hypothesis The retinoid hypothesis proposes that defects in genes (or their regulatory elements) which are involved in the retinoid pathway can cause CDH due to the importance of this pathway in normal diaphragm development in humans. This hypothesis is supported by evidence from dietary-induced, teratogen-induced, and genetic models of CDH (see Animal Models). Furthermore, this hypothesis is supported by direct evidence from studies of retinol and retinol binding protein (RBP) levels in newborns with CDH (see below). The STRA6gene has been directly linked to CDH in humans. This gene is a key cell surface receptor resonsible for transporting retinol into the target cell (see Figure). Mutations in STRA6 are responsible for Matthew-Wood syndrome. Deletions of the 15q24 region encompassing the STRA6 gene have also been observed in CDH patients. Genes involved in the retinoid signaling pathway are contained within genomic loci which display a strong association with CDH (see Genes) Studies in Humans Studies of the RA pathway in humans are limited. Recently, Beurskens et al found low levels of both retinol and retinol binding protein (RBP) in newborn infants with CDH compared to controls, independent of maternal retinol levels. These findings are suggestive of a defect in foetal retinoid homeostasis, and provide support for the retinoid hypothesis in human CDH . Lower levels of retinol and RBP in newborns with CDH were previously reported in one study . References